RNA interference is a natural mechanism that controls whether living cells use certain genes.
The discovery of RNA interference, which won the Nobel Prize in Physiology or Medicine in 2006, has since been used by scientists to create a powerful and growing class of drugs that can suppress disease-related genes. Seven such drugs have already received FDA approval, including inclisiran, which can replace daily cholesterol-lowering medications with semiannual injections. Despite these clinical successes, the molecular details of how the system performs the cuts remained poorly understood.
Now, scientists at the Scripps Research Institute have captured the first high-resolution structural images of the human RNA interference molecular machinery in a slice-ready state. Their findings were; Structural biology and molecular biology of nature June 24, 2026 Identify the precise atomic interactions that determine when and where a machine cuts. The structure shows which components of the protein are key to its function and provides a mechanistic explanation for how some RNA sequences are better at cleaving targets than others.
RNA interference has become a powerful platform for treating diseases, with more drugs entering the pipeline every year. But until now, we’ve been designing these drugs more or less in the dark. This study finally provides the structural picture needed to understand how to make and design better therapeutic siRNAs. ”
Ian McRae, professor at Scripps Research Institute and senior author of the new study
The challenge for drug developers is that for any given disease-causing gene, thousands of different siRNA sequences can shut down the corresponding target RNA. Developing new RNA interference drugs has been a long process of trial and error, as researchers cannot predict which ones will be successful without testing.
In the new study, co-lead authors Postdoctoral Researcher Sucharita Sarkar and Staff Scientist Luca Gebert in the McRae lab set out to determine the high-resolution structure of Argonaute 2 in its cleavage-ready state, bound to an siRNA molecule and ready to cleave the corresponding messenger RNA. Their problem was that this state lasted only a moment.
“The key was that we needed to come up with a special set of mutations that stabilized this active conformation,” Gebert says.
Once they identified these mutations, the researchers used cryo-electron microscopy (cryo-EM) to capture the atomic-level configuration of Argonaute 2 just before it cuts the RNA target. The structure revealed something surprising. Inside Argonaute 2, the RNA duplex targeted by the guide was physically distorted instead of maintaining its straight, natural conformation. This tailored transformation provided by Argonaute 2 places the precise chemical bonds that need to be severed directly within the protein’s molecular scissors.
“For the first time, we know exactly where two previously overlooked amino acids are located in the active site, and their locations have redefined the way we understand Argonaute 2 catalysis,” Sarkar says.
These two amino acids, lysine 709 and arginine 710, help facilitate the cleavage reaction, along with four other amino acids already known to be important for RNA cleavage. Lysine 709 acts as a molecular checkpoint, keeping it away from the active site until extended guide-target pairing causes duplex deformation and releases it to the cleavage site. Arginine 710 fine-tunes catalytic efficiency by sensing specific locations on target RNA. This illustrates a long-standing but poorly understood rule of thumb in siRNA design.
This new study not only describes a critical step in RNA interference, but may also provide concrete guidance on how to design siRNA molecules that are likely to be most effective. Sequences and chemical modifications that allow the paired RNA to more easily adopt a distorted shape are predicted to favor activation by Argonaute 2, whereas sequences and chemical modifications that rigidify the central region are expected to inhibit activation.
McCrae said the study opens the door to so-called “rational design,” or engineering siRNA sequences based on structural principles rather than trial and error.
“This class of drugs is already great, but the drugs in development are only going to get more powerful,” he says. “Understanding the mechanisms at this level should allow us to design better drugs from the start, potentially expanding the range of diseases that can be treated with RNA interference.”
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Scripps Research Institute
Reference magazines:
Sarkar, S. others. (2026). Catalytic activation of human Argonaute 2 requires deformation of the RNA duplex. Structural biology and molecular biology of nature. DOI: 10.1038/s41594-026-01840-5. https://www.nature.com/articles/s41594-026-01840-5
